Siglecs as Immune Cell Checkpoints in Disease

Abstract

Sialic acid–binding immunoglobulin-type lectins (Siglecs) are expressed on the majority of white blood cells of the immune system and play critical roles in immune cell signaling. Through recognition of sialic acid–containing glycans as ligands, they help the immune system distinguish between self and nonself. Because of their restricted cell type expression and roles as checkpoints in immune cell responses in human diseases such as cancer, asthma, allergy, neurodegeneration, and autoimmune diseases they have gained attention as targets for therapeutic interventions. In this review we describe the Siglec family, its roles in regulation of immune cell signaling, current efforts to define its roles in disease processes, and approaches to target Siglecs for treatment of human disease.

Novel ACE2-Independent Carbohydrate-Binding of SARS-CoV-2 Spike Protein to Host Lectins and Lung Microbiota

“…Since the SARS-CoV-2 spike protein has been described to express highly processed sialylated complex-glycans at N165, N282, N801, N1074 and N1098 [10] we investigated whether these glycans could be a signature for the sialic-acid binding lectins (Siglecs), a family of carbohydrate receptors with immune-receptor tyrosine-based inhibition motif (ITIM) and known immune inhibitory signaling properties [23]. Using our solid-phase immunoassay screening-system, a library of different Siglecs (Siglec-3, Siglec-5, Siglec-7, Siglec-9 and Siglec-10) was explored for binding activity to SARS-CoV-2 spike protein.…”

“…Using our solid-phase immunoassay screening-system, a library of different Siglecs (Siglec-3, Siglec-5, Siglec-7, Siglec-9 and Siglec-10) was explored for binding activity to SARS-CoV-2 spike protein. Siglecs can be expressed on almost all immune cells, including B and T cells, monocytes, eosinophils, and macrophages [23]. Although Siglecs are bona fide Sialic-acids binding proteins, the literature is not consistent in assigning a specific sialylated pattern to each Siglec.…”

“…Siglec-3 is highly expressed on macrophages and monocytes; Siglec-9 on monocytes, neutrophils, conventional dendritic cells, NK and T cells; Siglec-10 on B cells, monocytes and eosinophils [24]. Different Siglecs have been implicated in T cell-mediated tolerance, alter B cell function and the inhibitory Siglec-9 and Siglec-10 were upregulated on tumor-infiltrating CD4+ and CD8+ T cells contributing to exhaustion of tumor T cell responses [23]. As shown in Figure 2 we observed a specific interaction of the SARS-CoV-2 spike protein with Siglec-3, Siglec-9 and Siglec-10.…”

Characterization of Sialic Acid-Binding Immunoglobulin-Type Lectins in Fish Reveals Teleost-Specific Structures and Expression Patterns

“…Since in mammals Siglecs are heterogeneously expressed in immune cells [39], we conducted a subsequent qPCR analysis to determine which immune-cell populations express Siglecs in maraena whitefish. To this end, we isolated the HKs ( Figure 3A1) and extracted cells from these tissues ( Figure 3A2).…”

Isolation, identification, and characterization of the human airway ligand for the eosinophil and mast cell immunoinhibitory receptor Siglec-8

“…1 Among the leukocyte cell surface receptors that downregulate and resolve ongoing inflammatory responses are Siglecs, sialic acid-binding immunoglobulin-like lectins comprising a family of 14 human proteins, most of which are expressed on overlapping subsets of immune cells and most of which carry intracellular immunoreceptor tyrosine-based inhibitory motifs. 2 Among these, Siglec-8, which is expressed selectively on human eosinophils, mast cells, and basophils, 3,4 can significantly downregulate allergic inflammation and is under investigation as a therapeutic target in eosinophil-and mast cell-mediated diseases. 5,6 Siglecs bind to sialic acid-containing glycans (sialoglycans) on cell surfaces or are secreted into the local cellular milieu of inflammatory target tissues.…”